PROJECT SUMMARY: Delirium is a clinical syndrome characterized by acute and reversible disturbance in mental function that occurs in the elderly following metabolic abnormalities, surgery or infection. Individuals with Alzheimer's disease (AD) are more prone to developing delirium and despite resolution of the initial acute symptoms, frequently suffer an acceleration in the expected rate of cognitive decline with poor long-term outcomes. The precise mechanisms responsible for the exacerbation of the chronic neurodegenerative processes are poorly understood, significantly impeding the development of therapeutic interventions. This application aims to explore complex neuro-immune interactions, and identify mechanisms underlying progressive post-delirium cognitive decline. Specifically, we will explore newly discovered neuroprotective functions of microglia and test the hypothesis that such functions become impaired during systemic infection/inflammation, leading to exacerbation of neurodegeneration. We hypothesize that molecular manipulation of key cellular targets during acute systemic inflammation will preserve the neuroprotective microglia functions, reduce neurodegeneration and improve long-term cognitive outcomes. We have developed a sophisticated set of tools to test these hypotheses in vivo, including longitudinal high- resolution optical imaging of amyloid plaques, microglia and neurons, as well as calcium imaging, molecular/pharmacological manipulations and behavioral phenotyping. This project will significantly improve our understanding of the role of microglia in AD and has the potential to uncover novel therapeutic targets for the prevention of post-delirium progressive cognitive decline.